Calcium homeostasis is important in the regulation of cellular behavior as it is paramount in regulation of signaling events as well as other cellular and molecular functions. (Cole and Kohn, Cancer and Metastasis Rev. (1993). Carboxyamido-triazole (CAI) is an inhibitor of stimulated calcium influx through voltage gated and nonvoltage-gated calcium influx. It has been shown to inhibit important downstream signaling events including the release or arachidonic acid, production of inositol triphosphate in response to phosphorylation and activation of phospholipase A2, and tyrosine phosphorylation in response to receptor activation (Felder, et al. J. Pharm. Exp. Therap., 257:967-971 (1991); Gusovsky, et al. J. Bio. Chem., 268:7768-7772 (1993)). These signalling pathways regulate proliferation and other cellular events including adhesion, migration, and production of proteases. (Kohn, et al. Cancer Res. (1994) in press, Kohn, et al. Proc. Natl. Acad. Sci. U.S.A., communicated; Kohn and Liotta, J. Nat. Cancer Inst., 82:54-60 (1990)).
Carboxyamido-triazole (CAI) has been observed to inhibit malignant proliferation, invasion, and metastasis of cancer cells, suggesting the role of CAI, and related compounds, as potential cancer therapeutics (see U.S. Pat. No. 5,359,078). Of concern in the development and utilization of cancer therapeutics is the development of resistance by minor cells to the particular pharmacological regimen to which they are exposed.
Where such a resistance appears it is desirable to ascertain the resistance in order to devise therapeutics that obviate or prohibit the appearance of such resistance. When the resistance is associated with altered gene expression, isolation of the gene encoding proteins associated with the appearance of the resistance not only aids in the elucidation of the mechanism of drug resistance, but also provides useful markers for detecting the acquisition of the resistance as well as useful targets for intervention. The present invention provides an isolated CAI resistance (CAIR) gene whose expression is correlated with CAI resistance. This invention also provides for the protein encoded by this gene. The isolation of this gene and protein provide the aforementioned and other advantages.